Magnetic resonance imaging monitors physiological changes with antihedgehog therapy in pancreatic adenocarcinoma xenograft model.
OBJECTIVE
The sonic hedgehog (Shh) pathway has an established role in pancreatic cancer (pancreatic adenocarcinoma [PDAC]). We tested whether magnetic resonance imaging measures of vascular volume fraction (VVF) using magnetic iron oxide nanoparticles are sensitive to the antiangiogenic effect of targeted Shh therapies in a PDAC xenograft model.


METHODS
Pancreatic adenocarcinoma xenograft lines were subcutaneously implanted into nude mice (n = 19 samples within 4 groups). Therapies were targeted to 3 loci of the Shh signaling pathway (anti-Shh antibody, cyclopamine, or forskolin). Magnetic resonance imaging (4.7-T Bruker Pharmascan) was performed (after 1 week of intraperitoneal therapy) before and after intravenous injection of MION-47. Vascular volume fraction was quantified as DeltaR2 (from multicontrast T2 sequences) and normalized to an assumed VVF in muscle of 3%. Linear regression compared VVF to histological indices including microvessel density (MVD), viable gland density (VGD), and proliferative index (PI).


RESULTS
In response to anti-Hh treatment, tumors showed a decrease in VGD, PI, MVD, and VVF compared with controls (P < 0.001). Vascular volume fraction was compared with histological indicators of response: PI (R2 = 0.88; P < 0.05), VGD (R2 = 0.87; P< 0.05), and MVD (R2 = 0.85; P < 0.05).


CONCLUSIONS
Magnetic resonance imaging VVF using magnetic iron oxide nanoparticles may serve as a noninvasive measure of biological response to Shh PDAC therapy with easy translation to the clinic.
Guimaraes
Alexander R
AR
Department of Radiology, Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown, MA, USA. aguimaraesl@partners.org
Rakhlin
Elena
E
Weissleder
Ralph
R
Thayer
Sarah P
SP
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003287:Contrast Media / Q000008:administration & dosage; D052203:Ferrosoferric Oxide / Q000008:administration & dosage; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D003287:Contrast Media; D053823:Hedgehog Proteins; C509239:SHH protein, human; D014704:Veratrum Alkaloids; C499827:monocrystalline iron oxide nanoparticle; D005576:Colforsin; D052203:Ferrosoferric Oxide; C000541:cyclopamine